Deuterated HGFR inhibitors and their uses

Abstract

The present invention discloses a deuterated HGFR inhibitor, as shown in the following formula I. The present invention relates to a deuterated HGFR inhibitor, a pharmaceutical composition and use thereof. The deuterated HGFR inhibitor drug described in the present invention can further improve the pharmacokinetic properties of the HGFR inhibitor, reduce the dosage and possible toxic side effects.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and specifically relates to deuterated HGFR inhibitor drugs and uses thereof. Background Art

[0002] Lung cancer is the cancer with the highest morbidity and mortality, accounting for 18% of the total number of cancer cases. Among the new lung cancer patients each year, the proportion of patients with non-small cell lung cancer (NSCLC) is as high as 85%. The formation of NSCLC is related to a variety of cancer-related gene mutations, and Met mutation is an important driver gene for the formation of NSCLC. Hepatocyte growth factor receptor (HGF) is the only known ligand of Met receptor, which can induce Met dimerization and enter the activation state, thereby causing cell growth and migration-related effects. At the same time, Met signal dysregulation can lead to abnormal activation of multiple downstream signaling pathways, including RAS / MAPK pathway, PI3K / Akt pathway, etc., leading to the occurrence and deterioration of cancer. Inhibiting HGF binding, thereby inhibiting Met-mediated downstream signaling protein phosphorylation, can block the proliferation and survival of Met-dependent cancer cells.

[0003] Deuterated drugs, that is, new drug molecules in which one or more carbon-hydrogen bonds of a drug molecule are replaced with carbon-deuterium bonds, can improve the pharmacokinetic properties of the original drugs, thereby overcoming the original defects of the drugs such as easy metabolism and large side effects.

[0004] The present invention is a deuterated HGFR inhibitor drug, which can further improve the pharmacokinetic properties of current HGFR inhibitor drugs and reduce the dosage and possible toxic side effects. Summary of the invention

[0005] The present invention provides deuterated compounds of deuterated HGFR inhibitors and pharmaceutically acceptable salts thereof, which can further improve the pharmacokinetic properties of deuterated compounds of KRAS inhibitors and pharmaceutically acceptable salts thereof, and reduce the dosage and possible toxic side effects.

[0006] In order to achieve the above object, the present invention provides a deuterated compound of an HGFR inhibitor as shown in the following formula I and a pharmaceutically acceptable salt thereof:

[0007]

[0008] The deuterated compounds of HGFR inhibitors and pharmaceutically acceptable salts thereof of the present invention include the following structures:

[0009]

[0010] The deuterated compound of the HGFR inhibitor of the present invention and its pharmaceutically acceptable salt, wherein the pharmaceutically acceptable salt is selected from methanesulfonate, maleate, hydrochloride or phosphate.

[0011] The deuterated compound and pharmaceutically acceptable salt thereof of the present invention include use thereof in preparing anti-tumor drugs.

[0012] The deuterated compound and the pharmaceutically acceptable salt thereof of the present invention comprise the deuterated compound and the pharmaceutically acceptable salt thereof as active ingredients and a pharmaceutically acceptable carrier.

[0013] The pharmaceutical composition of the deuterated compound and the pharmaceutically acceptable salt thereof of the present invention is selected from capsules, powders, tablets, granules, pills, injections, syrups, oral liquids, inhalants, ointments, suppositories or patches. Beneficial effects: Compared with the prior art, the present invention has the following advantages:

[0014] The present invention provides a class of deuterated HGFR inhibitor drugs, which further improve the pharmacokinetic properties of HGFR inhibitors and reduce the dosage and possible toxic side effects. DETAILED DESCRIPTION

[0015] The present invention will be further described below with reference to the embodiments.

[0016] Example 1

[0017] Synthesis method

[0018]

[0019] Intermediate 1 can be prepared by referring to the method of patent CN103122000A (Example 44);

[0020] Synthesis of intermediate 2

[0021] Potassium hydroxide (4 mmol, 4 eq) and elemental iodine (2 mmol, 2 eq) were added to a solution of 0.424 g of intermediate 1 (1.0 mmol) in N,N-dimethylformamide (20 mL), and the mixture was reacted at room temperature for 3 hours. After the reaction was completed as monitored by TLC, a saturated sodium sulfite solution was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (10 mL*2), washed with water (20 mL*2), washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, and concentrated by column chromatography to obtain 0.41 g of intermediate 2 with a yield of 61%.

[0022] Synthesis of Example 1 Compound:

[0023] To a deuterated acetic acid solution (8 mL) of 0.34 g of intermediate 2 (0.5 mmol) was added sodium acetate (1 mmol, 2 eq) and the mixture was added dropwise over 2 hours. The mixture was reacted at room temperature for 24 hours. The reaction was complete when detected by TLC. The mixture was concentrated under reduced pressure and column chromatography was performed to obtain 0.17 g of Example 1 compound in a yield of 79%. 1 H NMR (400MHz, DMSO-d6) δ8.63 (s, 1H), 8.45 (s, 1H), 8.38 (d, J = 5.7Hz, 1H), 7.89 (s, 2H) ,7.83(d,J=3.7Hz,1H),7.50(d,J=3.7Hz,1H),3.82–3.80(m,4H),1.07–1.01(m,4H).

[0024] Example 2

[0025]

[0026] Intermediates 3 and 6 can be prepared by referring to patent CN103122000A (synthetic route of Example 44).

[0027] Intermediates 4 and 5 can be prepared by referring to the synthesis method of Example 1.

[0028] Synthesis of Example 2 Compounds:

[0029] 0.222 g of intermediate 5 (1.0 mmol, 1 eq) and 0.257 g of intermediate 6 (1.0 mmol, 1 eq) and methanesulfonic acid (1.2 mmol, 1.2 eq) were dissolved in 1-methoxy-2-propanol and stirred at 90° C. After 16 hours, the reaction was complete as monitored by TLC. After concentrating and drying the solvent, the mixture was purified by HPLC to obtain 0.296 g of Example 2 compound with a yield of 70%. 1 H NMR(300MHz,Chloroform-d)δ8.94(s,1H),7.99(s,1H),7.88(s,1H),7.74(s,2H),7.4 3(s,1H),3.85–3.72(m,4H),1.25(dd,J=8.8,5.5Hz,2H),1.13(dd,J=9.0,5.7Hz,2H).

[0030] Example 3

[0031] Referring to the synthesis method of the compound in Example 2, the compound in Example 3 can be prepared with a yield of 69%. 1H NMR(300MHz,Chloroform-d)δ8.96(s,1H),7.93(s,1H),7.78(s,2H),7.50(s,1H),7.4 6(s,1H),3.84–3.72(m,4H),1.22(dd,J=8.9,5.6Hz,2H),1.15(dd,J=9.0,5.7Hz,2H).

[0032] Test Example 1: c-Met kinase inhibitory activity test

[0033] (I) Reagents and consumables

[0034] Reagent name Suppliers Part Number c-Met kinase Cisbio 63ADK000CB16PEG 384-well plate PerkinElmer 6007290

[0035] (II) Instruments

[0036] Centrifuge (Manufacturer: Eppendorf, Model: 5430)

[0037] Microplate reader (Manufacturer: Perkin Elmer, Model: EnVision )

[0038] (III) Experimental methods

[0039] The compounds of Example 1-3 and Bozitinib were prepared with DMSO, diluted in proportion and added to 384 wells, c-Met kinase (final concentration 12.5 nM) and compound (DMSO final concentration 0.5%) were pre-incubated at 30°C for 20 minutes, ATP (final concentration 2.5 μM) and reaction substrate (final concentration 50 μM) were added after pre-incubation, reacted at 30°C for 1 hour, centrifuged at 1000 rpm for 30 seconds, shaken evenly and incubated at room temperature for 2 hours. The reading was read with an ELISA reader, Em665 / 620.

[0040] Compound <![CDATA[c-Met IC 50 (nM)]]> Example 1 22 Example 2 35 Example 3 20 Bozitinib 37

[0041] The compounds of the examples have excellent c-Met inhibitory activity. Compared with the positive drug bozitinib, the compounds of the examples have comparable activity. Some compounds, such as Example 3, have significantly better activity than the positive drug.

[0042] Experimental Example 2: Pharmacokinetics of Compounds

[0043] 1. Experimental instruments and materials

[0044] High-speed refrigerated centrifuge, vortex oscillator (Vortex Genius3), high-speed centrifuge (Eppendorf5415D), disposable syringes, pipettes (Eppendorf), SD male rats used in the experiment were purchased from Yangzhou University, EDTA-K2 vacuum blood collection tubes, and normal saline. All rats in the oral group fasted for 12 hours before administration, and had free access to water and food during administration.

[0045] (II) Experimental steps

[0046] Example 1 or bozitinib was dissolved in DMSO / solutol / water (10 / 10 / 80) to prepare a clear solution, and the compound dose for oral administration was 25 mg / kg, and the compound dose for tail vein administration was 5 mg / kg. At 2min, 10min, 30min, 1h, 2h, 3h, 5h, 8h, 12h, 16h, and 24h after tail vein administration, 0.5mL of blood was continuously taken from the fundus venous plexus into a heparin tube, and 5min, 15min, 30min, 1h, 2h, 3h, 5h, 8h, 12h, 16h, and 24h after oral administration, 0.5mL of blood was continuously taken from the fundus venous plexus into a heparin tube. After the sample was centrifuged at 8000r and 4°C for 10min, 0.15mL of upper plasma was taken and stored at -20°C, and then LC-MS / MS analysis was performed. The data was analyzed by WinNolin non-compartmental model to obtain key pharmacokinetic parameters.

[0047] (III) Experimental results

[0048] Table 1 Pharmacokinetic parameters

[0049]

[0050] Compared with the positive drug bozitinib, the oral half-life and peak concentration of Example 1 are significantly improved, and the oral bioavailability is also significantly improved, which can effectively improve the dosage of bozitinib, thereby reducing the toxic and side effects of high-dose administration of bozitinib.

[0051] Finally, it is necessary to explain that the specific embodiments of the present invention are described in detail above, but they are only examples, and the present invention is not limited to the specific embodiments described above. For those skilled in the art, any equivalent modifications and substitutions made to the present invention are also within the scope of the present invention. Therefore, the equalization changes and modifications made without departing from the spirit and scope of the present invention should be included in the scope of the present invention.

Claims

1. A deuterated compound of an HGFR inhibitor and a pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from the following structures: 、 。 2. The deuterated compound and pharmaceutically acceptable salt thereof according to claim 1, characterized in that The pharmaceutically acceptable salt is selected from methanesulfonate, maleate, hydrochloride or phosphate.

3. Use of the deuterated compound and pharmaceutically acceptable salt thereof according to claim 1 in the preparation of HGFR inhibitor drugs.

4. A pharmaceutical composition, characterized in that The pharmaceutical composition is composed of the deuterated compound and a pharmaceutically acceptable salt thereof as claimed in claim 1 as an active ingredient and a pharmaceutically acceptable carrier.

5. The pharmaceutical composition according to claim 4, characterized in that The pharmaceutical composition is selected from capsules, powders, tablets, granules, pills, injections, syrups, oral solutions, inhalants, ointments, suppositories or patches.

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